Vilazodone (2) is marketed in the United States as Viibryd™ and is indicated for the treatment of major depressive disorder.

U.S. Pat. No. 5,532,241 discloses compounds that are useful as intermediates in the preparation of Vilazodone. Examples of compounds disclosed in U.S. Pat. No. 5,532,241 include piperidine and piperazine derivatives of the following Formula:
wherein Ind, Q, Z and R1 are defined therein. These compounds and their physiologically acceptable salts are active on the central nervous system.
U.S. Pat. No. 5,418,237 discloses that indole derivatives of the following Formula:
wherein Ind, Q and Ar are as defined therein, and their salts, are active on the central nervous system.
U.S. Pat. No. 6,509,475 discloses a process for the preparation of a compound of the following Formula:
or a salt thereof in a Friedel-Crafts acylation catalyzed by a Lewis acid metal halide.
Heinrich, T., et al. in J. Med. Chem. 2004, 47, 4684-4692 disclose synthesis and structure-activity relationships in a class of indolebutylpiperazines as dual 5-HT1A receptor agonists and serotonin reuptake inhibitors. Further disclosed is that systematic structural modifications of indolealkylphenylpiperazines led to improved selectivity and affinity within this class of 5-HT1A receptor agonists. Introduction of electron-withdrawing groups in position 5 on the indole raises serotonin transporter affinity, and the cyano group proved to be the best substituent here. 5-Fluoro and 5-cyano substituted indoles show comparable results in in vitro and in vivo tests, and bioisosterism between these substituents was supported by calculation of the molecular electrostatic potentials and dipole moments. Compounds showing promising in vitro data were further examined in ex vivo (p-chloroamphetamine assay) and in vivo (ultrasonic vocalization) tests. Optimization of the arylpiperazine moiety indicated that the 5-benzofuranyl-2-carboxamide was best suited to increase 5-HT transporter and 5-HT1A receptor affinity and to suppress D2 receptor binding. 5-{4-[4-(5-Cyano-3-indolyl)butyl]-1-piperazinyl}benzofuran-2-carboxamide 29 (vilazodone, EMD 68843) was identified as a highly selective 5-HT1A receptor agonist [GTPγS, ED50=1.1 nM] with subnanomolar 5-HT1A affinity [IC50=0.2 nM] and as a subnanomolar 5-HT reuptake inhibitor [RUI=0.5 nM] showing a great selectivity to other GPCRs (e.g., D2, IC50=666 nM).
Heinrich, T., et al. in ACS Med. Chem. Lett. 2010, 1, 199-203 disclose allosteric IGF-1R inhibitors. Further disclosed is that targeting allosteric protein sites is a promising approach to interfere selectively with cellular signaling cascades. The authors discovered a novel class of allosteric insulin-like growth factor-I receptor (IGF-1R) inhibitors. 3-Cyano-1H-indole-7-carboxylic acid {1-[4-(5-cyano-1H-indol-3-yl)butyl]piperidin-4-yl}amide (10) was found with nanomolar biochemical, micromolar, cellular IGF-1R activity and no relevant interference with cellular insulin receptor signaling up to 30 μM. The allosteric binding site was characterized by X-ray crystallographic studies, and the structural information was used to explain the unique mode of action of this new class of inhibitors.
Bottcher, H., et al. in Liebigs Annalen der Chemie 1988, 8, 749-752 disclose synthesis of 3-[4-(1,2,3,6-Tetrahydro-4-phenyl-1-pyridyl)butyl]-5-indolecarboxylic Acid, an Antihypertensive Agent with a Novel Mode of Action. Further disclosed is that the racemic drug chlormezanone is resolved into the enantiomers by HPLC on cellulose triacetate and a silica gel-bound phenylalanine polymer. By preparative column chromatography on cellulose triacetate, both enantiomers were obtained on gram scale. Their racemization rate was determined as a function of the pH value. Furthermore, on cellulose triacetate and on particular polyamides, structure analogues of chlormezanone were separated into enantiomers, some of them completely.
Wenkert, E., et al. in J. Org. Chem. 1986, 51, 2343-2351 disclose a synthesis of prenylated indoles. Further disclosed is that interaction of magnesium indolates and allyl oxides in the presence of bis(triphenylphosphine)nickel dichloride results in indole β-allylation, except in cases involving highly substituted indoles and allyl alcohols. This method permits the β-prenylation of indole and α-prenylation of ketones (by way of their magnesium enaminates). Base-induced interaction of ethynyldimethylcarbinyl chloride and indole under a variety of conditions yields β(β,β-dimethylvinyl)quinolone as well as variously dehydroprenylated indoles. α-Lithiation of N-(benzenesulfonyl) indole followed by treatment with prenyl bromide or β,β-dimethyl acrylyl chloride produces α-prenyl or α-oxoprenylindole derivatives, the sodium amalgam reduction of the former of which yields α-prenylindole, prenylindole and β-oxoprenylindole, the latter also being the product of the reaction of magnesium indolate and the acid chloride. Lithium aluminum hydride reduction of 1-(benzenesulfonyl)-3-oxoprenylindole affords an alcohol, whose base hydrolysis produces β-dehydroprenylindole, a compound whose dimerization has led previously to naturally occurring yuehchukene.
CN102267932 provides a process for preparation of a compound of the following formula:
wherein R is C1-C4 alkyl, Ph, p-Me Ph, or C1-C4 alkyl Ph. The invention further relates to the application of the compound above as key intermediate for preparing Vilazodone or its pharmaceutically acceptable salt.
CN102267985 discloses a preparation method for Vilazodone and hydrochloride thereof. The method comprises the following steps: reacting the following compound:
with a compound of formula:
in a solvent under action of alkaline substances and collecting Vilazodone as described in the following formula:
from resultants; reacting the obtained Vilazodone with hydrochloric acid in a solvent for salt formation so as to prepare Vilazodone hydrochloride as described in the following formula:

CN102690224 discloses a new method for preparing 3-(4-chlorobutyl)-1H-5-cyanoindole as a Vilazodone intermediate, comprising the following steps: step (1), a compound of the following formula:
is reacted with a compound of formula:
in the presence of an acylation catalyst in an organic solvent to form a compound of formula:
step (2), the compound above formed in step (1) is subjected to carbonyl reduction reaction in the presence of a reducing catalyst in the organic solvent.
CN102659660 relates to a preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole. The preparation method comprises the following steps: after dissolving 3-(4-chlorobutyryl)-5-cyano-1H-indole in a solvent, adding trifluoroacetic acid, adding sodium borohydride in batches, and treating the reaction liquid to obtain the 3-(4-chlorobutyl)-5-cyano-1H-indole.
CN102617558 provides a preparation method of Vilazodone, which comprises the following steps: reacting 5-cyanoindole, which is used as the initial raw material, with substituted phenylsulfonyl chloride under alkaline conditions, carrying out Friedel-Crafts reaction under the catalytic action of Lewis acid, reducing the product, and carrying out substitution reaction with 5-(1-piperazino)-benzofuryl-2-formamide to obtain the Vilazodone. The invention also provides three intermediate compounds related to the vilazodone preparation method.
CN102875440 discloses a preparation method of 3-(4-chlorobutyl)-5-cyanoindole which is shown as the following formula:
The preparation method comprises the steps as follows: carrying out following carbonyl reduction reaction on the following compound:
and a hydroboron reducing agent in the solvent under the catalyzing of Lewis acid to obtain the product, wherein Lewis acid is one or more of aluminium trichloride, magnesium chloride, zinc chloride and ferric chloride; and the hydroboron reducing agent is one or more of sodium borohydride, potassium borohydride, lithium borohydride and borane.
CN102875538 relates to a method for preparing 5-(4-[4-(5-cyan-3-indolyl)-butyl]-1-piperazinyl)benzofuran-2-formamide (Vilazodone) or hydrochloride thereof. The method comprises the following steps of: performing reaction between a compound of the following formula:
and a compound of the following formula:
in a solvent under the action of alkaline matter, and separating and purifying products to obtain Vilazodone; and salifying the Vilazodone and hydrochloric acid in the solvent to prepare Vilazodone hydrochloride. The invention also relates to a method for preparing the indole compound above.
CN102796037 relates to the field of chemical synthesis of medicines, particularly a 3-(4-(4-substituted-piperazino)-1-butyryl)indolyl-5-formonitrile and a preparation method thereof, and application of the compound for preparing an intermediate 3-(4-piperazino-1-yl-butyl)indolyl-5-formonitrile for synthesizing Vilazodone.
CN103058912 relates to a preparation method of 3-(4-chlorobutyl)indole-5-formonitrile. CN103058912 further teaches (4-chlorobutyl)indole-5-formonitrile is an important intermediate for synthesis of vilazodone hydrochloride. 5-Cyanoindole and 4-chlorobutyryl chloride as raw materials undergo a Friedel-Crafts acylation reaction and then the product is reduced by sodium borohydride/trifluoroacetic acid into 3-(4-chlorobutyl)indole-5-formonitrile.
Hu, B., et al. in Org. Process Res. Dev. 2012, 16, 1552-1557 disclose a scale-up synthesis of antidepressant drug Vilazodone. A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel-Crafts acylation of 1-tosyl-1H-indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH4/CF3COOH system coupled with ethyl 5-(piperazin-1-yl)-benzofuran-2-carboxylate hydrochloride, one-step deprotection and esterolysis, and the final ammonolysis led to the target molecule vilazodone in 52.4% overall yield and 99.7% purity.